Background: Bortezomib represents a significant advance in the treatment of relapsed/refractory myeloma, but its efficacy is limited by a number of resistance mechanisms including activation of the anti-apoptotic heat shock protein (HSP) and stress response pathways. CNTO 328 is an anti-IL-6 chimeric monoclonal antibody shown to have anti - myeloma activities in vitro. Because IL-6 signaling augments the HSP response, downregulation of IL-6 signaling may enhance bortezomib’s clinical anti-myeloma activity. Pre-clinical studies demonstrated that this combination had an additive to synergistic effect in inducing apoptosis in IL-6-dependent and independent multiple myeloma cell lines (Voorhees et al., 2007, in press).
Methods: In this safety lead-in cohort of a pivotal trial (clinicaltrials.gov), CNTO 328, 6 mg/kg, was administered by IV every 2 weeks in combination with bortezomib, 1.3 mg/m2, given by IV on days 1, 4, 8, and 11 every 3 weeks. Pateints received a maximum of four, 6-week treatment cycles, after which the bortezomib schedule was reduced to four, once weekly doses in a 5-week maintenance cycle. When disease progression was documented, oral dexamethasone was added at 20 mg and given on the day of, and day after each bortezomib infusion, for a maximum of two cycles. All later cycles included 20 mg dexamethasone given only on the day of bortezomib administration.
Results: Preliminary results from the first 6 patients are available. Pateint characteristics included median age of 68 years; B2M > 3.0 mg/L, (n = 4 pateints); CRP > 3.0 mg/L (3); a median of 2 prior regimens (range 1 – 3), and prior bone marrow or peripheral blood stem cell transplantation in three patients. Using the EBMT response criteria, three patients achieved confirmed partial responses (PRs). Additionally, two patients had unconfirmed PRs. One patient discontinued prior to confirmation, while a follow up assessment for the other patient is pending. The median number of cycles administered was 3. Two of the patients ended treatment prematurely, 1 due to disease progression and 1 due to adverse events. The remaining 4 patients continue on study. Grade 3/4 adverse events (AEs) considered possibly related to CNTO 328 and bortezomib include neutropenia (2 patients), leukopenia (1), lymphopenia (1), and bloody diarrhea (1).
Conclusion: Treatment with anti-IL-6 CNTO 328 in combination with bortezomib has been evaluated for safety and efficacy in the first 6 patients of an ongoing pivotal trial for the treatment of relapsed or refractory multiple myeloma. Initial activity observed with this combination is encouraging, and enrollment is continuing to explore its full potential.
Disclosure:Employment: David La Police, Mark DeWitte, Zhihui Lang MD, Robert E. Corringham are employees of Centocor. Ownership Interests:; David La Police, Mark DeWitte, Zhihui Lang , Robert E. Corringham own stock in Johnson & Johnson. Research Funding: Robert F Manges, Heather J Sutherland, Sundar Jagannath, Robert Z Orlowski, Jean Francois Rossi.